The compound (2R)-2-acetamido-N-benzyl-3-methoxypropanamide of Formula-I having an international non-proprietary name Lacosamide is an anticonvulsant drug for the treatment of central nervous system disorder such as epilepsy. It is also useful in the treatment of pain particularly diabetic neuropathic pain.

U.S. Pat. No. 5,773,475 for first time reported the preparation of Lacosamide of Formula-I by three different methods. In the first method, D-serine is esterified followed by treating the D-serine methyl ester with benzylamine to result the compound (2R)-2-amino-N-benzyl-3-hydroxypropanamide of Formula-II. The compound of Formula-II is acetylated with acetic anhydride in solvent dichloromethane to give the compound (2R)-2-acetamido-N-benzyl-3-hydroxypropanamide of Formula-III. The compound of Formula-III is methylated using methyl iodide in the presence of silver oxide and solvent acetonitrile to give Lacosamide of Formula-I.
The second method describes the process, wherein D-serine is protected with benzyloxycarbonyl chloride to give N-Benzyloxycarbonyl-D-serine of Formula-IV. The compound of Formula-IV on alkylation with methyl iodide in the presence of silver oxide and solvent acetonitrile yields the compound (2R)-methyl 2-(benzyloxycarbonylamino)-3-methoxypropanoate of Formula-V, and which is purified by flash column chromatography using silica gel and methanol-chloroform eluent before the next stage. The compound of Formula-V is hydrolyzed to give (2R)-2-(benzyloxycarbonylamino)-3-methoxypropanoic acid of Formula-VI. The compound of Formula-VI is cooled to −78° C. in tetrahydrofuran and reacted with isobutyl chloroformate in presence of N-methylmorpholine followed by reaction with benzylamine to yield the compound (2R)-benzyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate of Formula-VII. The compound of Formula-VII on hydrogenation using palladium on carbon gives deprotected compound (2R)-2-amino-N-benzyl-3-methoxy-propanamide of Formula-VIII. The compound of Formula-VIII is acetylated using acetic anhydride in the presence of solvent pyridine to give crude Lacosamide of the Formula-I. The crude compound is purified by flash column chromatography to give pure Lacosamide.
The third method described in the patent, wherein D-serine is first acetylated to give N-acetylserine, which is taken in tetrahydrofuran and cooled to −78° C. to react with isobutyl chloroformate in the presence of N-methylmorpholine followed by reaction with benzylamine to give (2R)-2-acetamido-N-benzyl-3-hydroxypropanamide of Formula-III. The compound of Formula-III is purified by flash column chromatography and taken for alkylation with methyl iodide in the presence of silver oxide and solvent acetonitrile to give Lacosamide of Formula I. The reaction sequence of above three methods can be represented in Scheme-1.

Another patent application U.S.2009143472, discloses the process for preparation of Lacosamide of Formula-I, wherein D-serine is treated with trimethylsilyl chloride to protect the hydroxyl group and then reacted with trityl chloride followed by deprotection of hydroxyl group to isolate the protected compound N-trityl-D-serine of Formula-IX. The compound of Formula-IX is alkylated with methyl iodide in the presence of sodium hydride and imidazole at −15 to −5° C. to get the compound O-methyl-N-trityl-D-serine of Formula-X. The compound of Formula-X is reacted with isobutyl chloroformate in presence of N-methylmorpholine and followed by reaction with benzylamine to get the compound (2R)-N-benzyl-3-methoxy-2-(tritylamino)propanamide of Formula-XI. The compound of Formula-XI on deprotection yields the compound (2R)-2-amino-N-benzyl-3-methoxypropanamide of Formula-VIII, which on acetylation with acetic anhydride in the presence of dimethylaminopyridine yields Lacosamide of Formula-I. The reaction sequence is as given in Scheme-2;

Another U.S. patent application U.S.2008027137 describes the preparation of Lacosamide of Formula-I, wherein N-protected D-serine is O-methylated with either using dimethyl sulfate in presence of phase-transfer catalyst and sodium hydroxide or with butyllithium and dimethyl sulfate to get the compound (2R)-2-(tert-butoxycarbonylamino)-3-methoxypropanoic acid of Formula-XII. The compound of Formula-XII is reacted with benzylamine as per the process disclosed earlier to get the compound (2R)-tert-butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate of Formula-XIII. Deprotection of the compound of Formula-XIII with hydrochloric acid yields the compound (2R)-2-amino-N-benzyl-3-methoxy-propanamide of Formula-VIII, which on acetylation yields the compound Lacosamide of Formula-I. The reaction sequence is as given in Scheme-3.

Another method for the preparation of Lacosamide of Formula-I was described in the Journal Bioorganic & Medicinal Chemistry, 16(19), 8968-8975 (2008), wherein D-serine methyl ester is treated with diethoxytriphenylphosphorane to give 9:1 mixture of (R)-aziridine-2-carboxylic acid methyl and ethyl ester of Formula-XIV. The mixture of compound of Formula-XIV on acetylation with acetic anhydride in the presence of triethylamine and dimethylaminopyridine gives a mixture of (R)-1-acetylaziridine-2-carboxylic acid methyl and ethyl ester of Formula-XV. The mixture of compound of Formula-XV is treated with methanol in the presence of borontrifluoride etherate BF3.Et2O to give a mixture of (2R)-2-acetamido-3-methoxypropanic acid methyl and ethyl ester of Formula-XVI. The compound of Formula-XVI on hydrolysis with lithium hydroxide yields the compound (2R)-2-acetamido-3-methoxypropanoic acid of Formula- XVII; which on reaction with benzylamine in presence of tetrahydrofuran and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride followed by purification of the product using flash column chromatography (10:90 MeOH/CHCl3) yields compound Lacosamide of Formula-I. The reaction sequence is as given in Scheme-4;

The drawbacks of the above described processes are:                i. Use of expensive D-serine or its derivatives as starting material;        ii. O-methylation involves the use of methyl iodide and silver oxide, which is expensive;        iii. Lower temperature required to carry out the amide formation reaction;        iv. The purification using flash column chromatography to purify the intermediates and the final compounds renders the process industrially unviable.        
It is therefore required to develop an alternative and improved process for the preparation of Lacosamide which overcomes the problems associated with the processes known in the art.
The present inventors ameliorates the problems of the prior art processes by using cost effective, naturally occurring starting material and avoiding the use of Flash column chromatography for the purification of product Lacosamide of Formula-I.